Multifunctional metal organic frameworks for enhancing mild-temperature photothermal therapy via inhibiting HSP expression

Hyperthermia induced by photothermal therapy can cause certain damage to surrounding healthy tissues and cells. In contrast, low-temperature photothermal therapy (LTPTT) has emerged as an alternative due to its non-invasiveness and safety. However, tumor cells can upregulate the molecular chaperone heat shock protein upon thermal stimulation, thereby compromising the therapeutic efficacy of LTPTT. Based on this, this study designed and developed ZIF-8 nanoparticles loaded with gambogic acid (GA), and modified the surface of these nanoparticles with Au nanoparticles to obtain the composite nano-system ZIF-8@Au@GA (ZAG). ZAG can accumulate in the tumor site through the enhanced permeability and retention effect and achieve LTPTT in synergy with an 808 nm laser. The loaded GA, as a natural inhibitor of heat-shock protein 90, can directly exert an anti-tumor effect. Meanwhile, the small-sized Au nanoparticles can act as glucose oxidase mimics to consume cellular ATP levels, further reversing the thermal tolerance of tumor cells, and can also upregulate reactive oxygen species such as H₂O₂ to kill tumor cells. Both in vitro and in vivo experiments have demonstrated that the designed ZAG composite system, in combination with an 808 nm laser, can achieve favorable LTPTT efficacy without any toxic side effects. This integrated dual-enhancement strategy for LTPTT designed in this study offers a new perspective for tumor therapy.